Cyclin D1 repression of peroxisome proliferator-activated receptor γ expression and transactivation

The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPARgamma induces hepatic steatosis, and liganded PPARgamma promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPARgamma function, transactivation, expression, and promoter activity. PPAR-gamma transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPARgamma ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPARgamma-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1(-/-) fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPAR gamma ligands of PPARgamma and PPARgamma-responsive genes, and cyclin D1(-/-) mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPARgamma in vivo. The inhibition of PPARgamma function by cyclin D1 is a new mechanism of signal transduction cross talk between PPARgamma ligands and mitogenic signals that induce cyclin D1.